Substrate coupling and inhibition in human Na+-dependent Cl-/HCO3- exchanger NCBE (SLC4A10)
Peixin Sun1,2,3, Xinmin Wang1,2,3, Yang Huang2
1Department of Hepatobiliary Surgery and Liver Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China.
Abstract:
Maintaining pH homoeostasis is essential for neuronal excitability and for regulating cerebrospinal fluid (CSF). The Na⁺-dependent Cl⁻/HCO3⁻ exchanger, NCBE (SLC4A10), abundant in the choroid plexus, contributes to CSF pH control by mediating bicarbonate flux, yet its molecular mechanism has remained unclear. Here we report cryo-EM structures of human NCBE in multiple functional states, revealing conserved binding sites for Na⁺, Cl⁻, and HCO3⁻, as well as an unexpected K⁺ site indicating relaxed cation selectivity. The inhibitor DIDS binds above the substrate cavity, locking NCBE in an outward-facing conformation and defining a subfamily-selective inhibitory mechanism. Functional assays and molecular dynamics simulations support the coordination of ions and the inhibitory effects. Comparison with an AlphaFold3-predicted inward-facing model suggests an elevator-like transport mechanism and delineates the conformational transitions in Na⁺-dependent HCO₃⁻ transporters. Together, these findings establish a structural framework for NCBE and offer insights into ion coupling and pharmacological modulation within the SLC4 family.
More Related Videos
05:27Inner Mitochondrial Membrane Sensitivity to Na+ Reveals Partially Segmented Functional CoQ Pools
Published on: July 20, 2022
06:59A Fluorescence-Based Assay of Membrane Potential for High-Throughput Functional Study of Two Endogenous Ion Channels in Two Epithelial Cell Lines
Published on: June 22, 2022
Related Concept Videos
Secondary Active Transport
Secondary Active Transport
Secondary Active Transport
The Significance of Membrane Transport
Transporters facilitate either an active or passive movement of solutes. They can allow a single-molecule transport down its...
Active Transport
Primary active transporters, like Na+, K+ and -ATPase, directly utilize ATP to move ions across the membrane. These transporters play significant roles in various physiological processes. For instance, Na+, K+ and -ATPase maintain...
Enzyme Inhibition
